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Acquired resistance to rechallenge injury in rats that recovered from mild renal damage induced by uranyl acetate: accelerated proliferation and hepatocyte growth factor/c-Met axis

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Abstract

Background

Rats that recovered from mild proximal tubule (PT) injury without renal dysfunction by subtoxic insult, developed partial resistance to subsequent nephrotoxic insult. This partial resistance was associated with reduced renal dysfunction and accelerated PT cell proliferation compared with vehicle treatment as the first insult. Here we assessed the role and potential mechanisms of accelerated PT proliferation in this acquired resistance model.

Methods

Rats at 14 days after recovering from prior mild renal damage induced by 0.2 mg/kg uranyl acetate (UA) (subtoxic dose) were rechallenged with 4 mg/kg UA (nephrotoxic dose) to establish the acquired resistance model. Cell cycle was inhibited by colchicine to examine the contribution of accelerated PT cell proliferation evaluated by in vivo bromodeoxyuridine (BrdU) labeling on acquired resistance to subsequent nephrotoxic insult. Hepatocyte growth factor (HGF)/c-Met axis and other related factors of cell cycle were analyzed.

Results

The acquired resistance to rechallenge injury with nephrotoxic dose of UA in rats recovered from mild renal injury was associated with an earlier increase in BrdU-positive PT cells, accelerated upregulation of HGF mRNA, c-Met mRNA/protein, cyclin D1, phospho-Rb and an earlier phenotypic change of PT cells. Colchicine inhibited PT cell proliferation, reduced the upregulated cyclin D1 and phospho-Rb in the kidney, completely abolishing acquired resistance.

Conclusions

Cell cycle progression with upregulated renal HGF/c-Met axis may contribute to the accelerated recovery from acute renal failure in rats that recovered from prior mild renal damage, followed by nephrotoxic insult, resulting in partial acquired resistance.

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Acknowledgments

This study was presented in part at the 40th annual meeting of the American Society of Nephrology, San Francisco, CA, 2007. This work was supported by a Grant-In-Aid for scientific research (C; No. 19590945) and (C; No. 22590884) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Conflict of interest

There is no declared conflict of interest in this study.

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Authors and Affiliations

  1. First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Yuan Sun, Yoshihide Fujigaki, Masanori Sakakima, Tomoyuki Fujikura, Akashi Togawa, Yanjie Huang & Akira Hishida

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  1. Yuan Sun
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  2. Yoshihide Fujigaki
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  3. Masanori Sakakima
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  7. Akira Hishida
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Correspondence to Yoshihide Fujigaki.

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Sun, Y., Fujigaki, Y., Sakakima, M. et al. Acquired resistance to rechallenge injury in rats that recovered from mild renal damage induced by uranyl acetate: accelerated proliferation and hepatocyte growth factor/c-Met axis. Clin Exp Nephrol 15, 666–675 (2011). https://doi.org/10.1007/s10157-011-0453-x

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  • DOI: https://doi.org/10.1007/s10157-011-0453-x

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